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Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice

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Abstract

Rationale

The novel antipsychotic aripiprazole in use for treatment of schizophrenia is a partial agonist at dopamine D2 receptors with actions at a variety of other receptors as well. Cocaine is believed to exert an important part of its rewarding effect by increasing extracellular levels of dopamine that subsequently act at dopamine D2 receptors.

Objectives

As a partial agonist, aripiprazole may antagonize effects at D2 receptors and we accordingly tested whether aripiprazole could antagonize self-administration of cocaine. Because D2-like receptor agonists are self-administered, a D2 receptor partial agonist like aripiprazole might itself be reinforcing. Thus, we also assessed whether mice would acquire self-administration of aripiprazole.

Materials and methods

A single session, mouse self-administration procedure was used.

Results

Oral pretreatment with aripiprazole dose-dependently decreased cocaine self-administration under a fixed ratio 1 schedule at the peak cocaine dose (0.03 mg/kg/infusion), reaching significance at 0.2 and 0.4 mg/kg of aripiprazole. Using 0.4 mg/kg, aripiprazole decreased rates of cocaine self-administration without shifting the peak of the dose-response function. There was no effect of aripiprazole per se, suggesting that its inhibitory action was due to effects on cocaine self-administration rather than non-specific motor effects. Aripiprazole was not found to be self-administered in the tested dose range (0.0003–0.3 mg/kg/infusion). The three highest doses (0.03, 0.1, and 0.3 mg/kg/infusion) even caused significant decreases in nose-poking activity, possibly due to extrapyramidal side effects.

Conclusions

These data are consistent with a potential role for aripiprazole in treatment of cocaine addiction without abuse potential per se.

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Acknowledgements

The authors wish to thank Dr. Rene Holm for the expert assistance on formulation of aripiprazole. In addition, excellent technical assistance by Mrs. Lisbet Petri, Mrs. Helle Porsdal, Mr. Leslie Griffiths, and Mrs. Rikke Madsen is highly appreciated.

The authors certify that there is no actual or potential conflict of interest in relation to this article.

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Authors and Affiliations

  1. Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark

    Gunnar Sørensen, Cecilie Hee Bengtsen, Gitta Wörtwein, Anders Fink-Jensen & David P. D. Woldbye

  2. Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Gunnar Sørensen, Cecilie Hee Bengtsen, Gitta Wörtwein, Anders Fink-Jensen & David P. D. Woldbye

  3. Division of Neurobiology, H. Lundbeck A/S, Copenhagen, Denmark

    Thomas N. Sager, Lise T. Brennum & Peter Thøgersen

  4. Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

    Jørgen H. Petersen

  5. Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Boston, MA, USA

    Morgane Thomsen

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  1. Gunnar Sørensen
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  2. Thomas N. Sager
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  10. David P. D. Woldbye
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Correspondence to David P. D. Woldbye.

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This work was supported by grants from the Augustinus Foundation, Ivan Nielsen Foundation, Lundbeck Foundation, Psychiatric Basic Research Foundation and Theodore and Vada Stanley Foundation.

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Sørensen, G., Sager, T.N., Petersen, J.H. et al. Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice. Psychopharmacology 199, 37–46 (2008). https://doi.org/10.1007/s00213-008-1069-z

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